JP2011102306A - 3,5,3'-triiodothyronine sulfate as thyroid hormone preparation and pharmaceutical formulation thereof - Google Patents

3,5,3'-triiodothyronine sulfate as thyroid hormone preparation and pharmaceutical formulation thereof Download PDF

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JP2011102306A
JP2011102306A JP2010288189A JP2010288189A JP2011102306A JP 2011102306 A JP2011102306 A JP 2011102306A JP 2010288189 A JP2010288189 A JP 2010288189A JP 2010288189 A JP2010288189 A JP 2010288189A JP 2011102306 A JP2011102306 A JP 2011102306A
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triiodothyronine
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Aldo Pinchera
アルド・ピンチェラ
Ferruccio Santini
フェルッチオ・サンチーニ
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Abstract

<P>PROBLEM TO BE SOLVED: To provide a drug effective for the treatment of pathologies due to organic deficiency of triiodothyronine (T3), for example, original hypothyroidism from autoimmune thyroid diseases, hormonal production defects, thyroidectomy, congenital hypothyroidism, as well as some disorders due to reduced activity of type I 5'-iodothyronine monodeiodinase (type I MD) which is induced, for example, by hypothyroidism, non thyroidal systemic illnesses, fast, and selenium shortage. <P>SOLUTION: There are provided a method of using triiodothyronine sulfate, as such or in association with thyroxine (T<SB>4</SB>), as a drug which activates thyroids, and pharmaceutical formulations therefor. <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

本発明は，３，５，３’−トリヨードチロニン硫酸塩（3,5,3’-triiodothyronine sulfate）の有機物欠乏症に起因する病状を治療するために，通常，トリヨードチロニン硫酸塩又はＴ３硫酸塩，或いはＴ３Ｓと名付けられる３，５，３’−トリヨードチロニン硫酸塩を活性成分として単独で，若しくはチロキシンと一緒に使用する方法に関する。 The present invention usually involves treatment with triiodothyronine sulfate or 3,5,3'-triiodothyronine sulfate to treat a condition caused by organic deficiency. T 3 sulfate or alone T 3 named S 3,5,3'-triiodothyronine sulfate as active ingredient, or on how to use with thyroxine.

血液中には，甲状腺で直接的に生成されるか，若しくは他のヨードチロニンの末梢代謝の結果物として，多数のヨードチロニンが存在する。それらの中でも，３，５，３’−トリヨードチロニン（頭文字Ｔ３）は,甲状腺ホルモン（ＴＨ）の生物学的活性型とみなされる。なぜならば，Ｔ３は，甲状腺ホルモンの特定の受容体に対して高親和性を示し，通常，この受容体を活性させるのに十分な濃度で血清中に存在するからである。 There are numerous iodothyronines in the blood, either produced directly in the thyroid or as a result of peripheral metabolism of other iodothyronines. Among them, 3,5,3′-triiodothyronine (acronym T 3 ) is considered a biologically active form of thyroid hormone (TH). Because, T 3 is because exhibits high affinity for a particular receptor for thyroid hormone, usually present in serum at a concentration sufficient to active the receptor.

成人健常者の甲状腺の主たる分泌物は，一般に頭文字Ｔ４と表されるチロキシンである。Ｔ４は，末梢組織で，Ｉ型及びＩＩ型の５’−ヨードチロニンモノ脱ヨード酵素（5’-iodothyronine monodeiodinases）の両方（それぞれ，Ｉ型ＭＤ及びＩＩ型ＭＤと呼ぶ）によって，分子の外側芳香族環からヨウ素原子が酵素除去され，その生物学的活性型であるＴ３（非特許文献１参照）に変換される。この代謝経路は，Ｔ３を内因的に生産する主たる機構であり，従って，Ｔ４はプロホルモンと考えるのが適切である。一方，Ｔ３の一部は，甲状腺によっても直接的に分泌される。平均して，体重７０ｋｇの成人１人が生産するＴ４の量は，１００μｇ／日に達するのに対して，Ｔ３の総生産量は，約２５μｇに達する。この２５μｇのうち，４〜８μｇのＴ３は，甲状腺によって直接的に分泌され，残りは，末梢組織でのＴ４の転換から生じる。 The main secretion of healthy adult thyroid are generally thyroxine, denoted acronym T 4. T 4 is a molecule of peripheral molecules that is expressed by both type I and type II 5′-iodothyronine monodeiodinases (referred to as type I MD and type II MD, respectively). The iodine atom is removed from the outer aromatic ring by an enzyme, and the biologically active form T 3 (see Non-Patent Document 1) is converted. This metabolic pathway is the main mechanism to produce T 3 endogenously, thus, T 4 is suitably to think that prohormones. On the other hand, a part of T 3 is secreted directly by the thyroid. On average, the amount of T 4 produced by an adult weighing 70 kg reaches 100 μg / day, while the total production of T 3 reaches about 25 μg. Of this 25 μg, 4-8 μg of T 3 is secreted directly by the thyroid gland, with the remainder resulting from T 4 conversion in peripheral tissues.

Ｔ３は，２つの異なる代謝経路がある。主たる代謝経路は，ＩＩＩ型５−ヨードチロニンモノ脱ヨード酵素（ＩＩＩ型ＭＤ）によって，内側芳香族環を部分的に脱ヨード化して３，３’−ジヨードチロニンを得るものである。この３，３’−ジヨードチロニンは，生物学的に非活性で，脱ヨード化又は硫酸抱合（sulfoconjugation）を介してさらに代謝される。他方の代謝経路は，身体によって生成されるＴ３の総量の約２０％に関し，Ｔ３の硫酸抱合を増進させてＴ３Ｓを得る。このＴ３Ｓは，甲状腺ホルモンと結合できないので（非特許文献２参照），従って，生物学的に非活性である（非特許文献３参照）。 T 3, there are two different metabolic pathways. The main metabolic pathway is to obtain 3,3′-diiodothyronine by partially deiodating the inner aromatic ring with type III 5-iodothyronine monodeiodinase (type III MD). This 3,3′-diiodothyronine is biologically inactive and is further metabolized via deiodination or sulfate conjugation. The other metabolic pathway relates about 20% of the total amount of T 3 produced by the body to obtain a T 3 S by enhancing the sulfoconjugation of T 3. This T 3 S cannot bind to thyroid hormone (see Non-Patent Document 2) and is therefore biologically inactive (see Non-Patent Document 3).

Ｔ３とは違い，Ｔ３Ｓは，ＩＩＩ型ＭＤによって脱ヨード化されない。むしろ，Ｔ３Ｓは，Ｉ型ＭＤ（非特許文献４参照）に対する優秀な基質であり，それによって，非常に迅速に３，３’−ジヨードチロニン硫酸塩に転換される。その結果，成人健常者において，Ｔ３を硫酸抱合してＴ３Ｓを得ることは，Ｔ３の異化代謝の速度を上げて，その胆汁及び尿の排出を容易化する一方法を示していることが，広く知られた常識になった。実際に，健常な成人では生理学的に低いＴ３Ｓの血清中濃度は，Ｉ型ＭＤの活性が低減されると高くなることが判明した。 Unlike T 3, T 3 S is not deiodination by type III MD. Rather, T 3 S is an excellent substrate for type I MD (see Non-Patent Document 4) and is thereby converted to 3,3′-diiodothyronine sulfate very quickly. As a result, in healthy adults, it the T 3 to obtain a T 3 S in conjugation sulfuric acid, to increase the rate of catabolism of T 3, illustrates one method of facilitating the discharge of the bile and urine That became common knowledge. In fact, in healthy adults, it was found that physiologically low serum concentrations of T 3 S increase when the activity of type I MD is reduced.

しかしながら，予想外なことに，身体において部分及び器官によっては，特定の生理学的条件及び状況の下で，Ｔ３Ｓを再度，その活性型のＴ３に転換することが可能なスルファターゼが存在することも判明した（非特許文献７〜９参照）。 Unexpectedly, however, there are sulfatases that, depending on parts and organs in the body, can convert T 3 S back to its active form of T 3 under certain physiological conditions and circumstances. It has also been found (see Non-Patent Documents 7 to 9).

そのような酵素は，肝臓，腎臓及び中枢神経系等の身体の組織内，並びに腸内のミクロフロラ内に知られている（非特許文献１０）。   Such an enzyme is known in body tissues such as the liver, kidney and central nervous system, and in the microflora in the intestine (Non-patent Document 10).

近年，子宮内生活の間，内因性Ｔ３Ｓの血清中濃度が，非常に高くなっており，そのような状況，即ち，成人で一般的に知見される値よりも高くなっている状況が，少なくとも出生後生活４ヶ月目までは，身体によって保持されることが判明した（非特許文献１１参照）。成長の際に，甲状腺ホルモンが果たす本質的な役割を考えると，特に中枢神経系の機能が関係している限りにおいては，この組織内で，人生の第１期（the first period of life）の間，必要な場合及び時に応じて，Ｔ３ＳがＴ３の予備の供給源として身体によって使用される可能性もあると推測される。解剖後のヒトの神経大脳組織の検死解剖試験片（autoptic specimens）上で行われた研究によって，同一結果中のＴ３の量がＩＩＩ型ＭＤによって制限されることが示された（非特許文献１２参照）。この酵素は，Ｔ３Ｓを攻撃しないが，Ｔ３Ｓをその活性型に再度，転換可能なスルファターゼを含有する組織内でＴ３ホルモンが特別に必要となった場合に，例外的にＴ３ホルモンの代替的な内因性供給源の役割を果たし得ることが推量される（非特許文献８，１３参照）。 In recent years, serum levels of endogenous T 3 S have become very high during in utero life, such a situation, that is, higher than commonly found in adults. , It was found that it was held by the body at least until the fourth month of life after birth (see Non-Patent Document 11). Given the essential role played by thyroid hormones during growth, the first period of life within this organization, especially as far as central nervous system function is concerned. In the meantime, it is speculated that T 3 S may be used by the body as a spare source of T 3 as needed and sometimes. Studies performed on post-dissection human neuro-cerebral tissue on autoptic specimens have shown that the amount of T 3 in the same result is limited by type III MD (non-patent literature) 12). This enzyme does not attack T 3 S, when T 3 hormone becomes specially required in the tissue where again T 3 S into its active form, containing convertible sulfatase, exceptionally T 3 It is speculated that it may serve as an alternative endogenous source of hormones (see Non-Patent Documents 8 and 13).

甲状腺ホルモンを生成及び代謝する際に，Ｔ３Ｓが果たす効果的な役割を解明するように，さらなる研究が行われた。この研究によって，それが，甲状腺機能正常ラット（非特許文献１４参照）及び甲状腺機能低下ラット（非特許文献１０参照）で，甲状腺ホルモン様効果を示すことが最近，実証された。いずれの場合にも，Ｔ３Ｓは，Ｔ３の約１／５の効果を示した。さらに，Ｔ３Ｓを用いた治療及びＴ３を用いた治療の両方で，甲状腺正常ラットの血清中の甲状腺刺激（thyreotropic）ホルモン（ＴＳＨ）の濃度が著しく減少した。即ち，その分泌を抑制する点で類似の能力を有することを示した。これに対して，甲状腺機能低下ラットでは，Ｔ３Ｓは，ＴＳＨの抑制において，Ｔ３と比較して貧弱な性能を示した。ＴＳＨが，甲状腺の機能状態に非常に反応性の高い指標であり，且つそのホルモン分泌の微細な変化を検出可能にすることはよく知られている。実際に，甲状腺機能性が低下した条件下では，無症状として定義付けられる状態においてさえ，Ｔ３Ｓの濃度は，より高くなっている。一方，甲状腺ホルモンが過剰に存在する場合，それらは減少する。従って，Ｔ３Ｓは，ＴＳＨの形成を抑制する能力に関与する限りは，予想に反してＴ３と比較にならないと思われる。 Further studies were conducted to elucidate the effective role that T 3 S plays in producing and metabolizing thyroid hormone. This study has recently demonstrated that it exhibits a thyroid hormone-like effect in rats with normal thyroid function (see Non-Patent Document 14) and hypothyroid rats (see Non-Patent Document 10). In any case, T 3 S showed an effect about 1/5 of T 3 . Furthermore, both the treatment with T 3 S and the treatment with T 3 significantly reduced the concentration of thyreotropic hormone (TSH) in the serum of normal thyroid rats. That is, it showed that it has a similar ability in suppressing its secretion. In contrast, in hypothyroid rats, T 3 S showed poor performance compared to T 3 in suppressing TSH. It is well known that TSH is an index that is very responsive to the functional state of the thyroid gland and that it can detect minute changes in its hormone secretion. In fact, under conditions of reduced thyroid function, the concentration of T 3 S is higher even in a state defined as asymptomatic. On the other hand, if thyroid hormones are present in excess, they decrease. Thus, T 3 S appears to be incomprehensible to T 3 as long as it is involved in the ability to suppress TSH formation.

結論として，特に最新の研究を考慮すると，Ｔ３Ｓによって果たされる生物学的な役割は，まだ明確且つ完全な知識に到達していない。 In conclusion, especially considering the latest research, the biological role played by T 3 S has not yet reached a clear and complete knowledge.

実際に，その主たる，根拠十分な，且つ普遍的に受入れられている特性は，その非生物学的な活性（即ち，Ｔ３の生物学的に不活性な代謝産物であること（非特許文献２及び３）），及び硫酸化経路がＴ３の異化代謝の代謝活性剤とみなされていることである（非特許文献５参照）。 In fact, its main, well-founded, and universally accepted property is its non-biological activity (ie, the biologically inactive metabolite of T 3 (non-patent literature). 2 and 3)), and that the sulfation pathway is regarded as a metabolic activator of catabolism of T 3 (see Non-Patent Document 5).

他方，特定の組織内で，且つそれら組織内で甲状腺ホルモンの欠乏に起因する例外的で決定的な条件下においてのみ，Ｔ３Ｓは，Ｔ３の内因性の局所的供給源としてのその能力を示した。 On the other hand, only within exceptional tissues and under exceptional and critical conditions due to thyroid hormone deficiency in these tissues, T 3 S is able to function as an endogenous local source of T 3. showed that.

Chopra IJ.著「Nature, source and relative biological significance of circulating thyroidhormones.」Braveman LE., Utiger RD. 編集, The Thyroid, Lippincott, Philadelphia 1991年, １２６〜１４３頁Chopra IJ. “Nature, source and relative biological significance of circulating thyroidhormones.” Braveman LE., Utiger RD., The Thyroid, Lippincott, Philadelphia 1991, 126-143. Spaulding SW., Smith TJ., Hinkle PM., Davis FB., Kung MP., Roth JA.著「Studies on the biological activity of triiodothyronine sulfate.」, J. Clin. Endocrinol. Metab 誌 1992年, 74巻, １０６２〜１０６７頁Spaulding SW., Smith TJ., Hinkle PM., Davis FB., Kung MP., Roth JA., "Studies on the biological activity of triiodothyronine sulfate.", J. Clin. Endocrinol. 1062 to 1067 Lo Presti JS., Mizuno L., Nimalysuria A., Anderson KP., Spencer CA., Nicoloff JT.著「Characteristic of 3,5,3’-triiodothyronine sulfate metabolism in euthyroidman.」, J. Clin. Endocrinol. Metab 誌 1991年, 73巻, ７０３〜７０９頁Lo Presti JS., Mizuno L., Nimalysuria A., Anderson KP., Spencer CA., Nicoloff JT., "Characteristic of 3,5,3'-triiodothyronine sulfate metabolism in euthyroidman.", J. Clin. Endocrinol. Metab Journal 1991, 73, 703-709 Santini F., Hurd RE., Chopra IJ 著「A study of metabolism of deaminated and sulfoconjugated iodothyronines by rat placental iodothyronine 5-monodeiodinase.」Endocrinology誌 1992年, 131巻, 4号, １６８９〜１６９４年Santini F., Hurd RE., Chopra IJ, "A study of metabolism of deaminated and sulfoconjugated iodothyronines by rat placental iodothyronine 5-monodeiodinase." Endocrinology 1992, 131, 4, 1689-1694 Otten MH., Mol JA., Visser TJ.著「Sulfation proceding deiodination of iodothyronines in rat hepatocytes.」Scinece誌1983年, 221巻, ８１〜８３頁Otten MH., Mol JA., Visser TJ. “Sulfation proceding deiodination of iodothyronines in rat hepatocytes.” Scinece 1983, 221, 81-83 Mol JA., Visser TJ.著「Rapid and selective inner ring deiodination of T4 sulfate by rat liver deiodinase.」Endocrinology誌1986年, 117巻, ８〜１２頁Mol JA., Visser TJ. “Rapid and selective inner ring deiodination of T4 sulfate by rat liver deiodinase.” Endocrinology 1986, 117, 8-12 Kung MP., Spaulding SW., Roth JA.著「Desulfation of 3,5,3’-triiodothyronine sulfate by microsomes from human and rat tissues.」Endocrinology誌1988年, 122巻, １１９５〜１２００頁Kung MP., Spaulding SW., Roth JA. "Desulfation of 3,5,3'-triiodothyronine sulfate by microsomes from human and rat tissues." Endocrinology 1988, 122, 1195-1200 Santini F., Chopra IJ., Wu SY., Solomon DH., Chua Teco GN.著「Metabolism of ３，５，３’-triiodothyronine sulfate by tissues of the fetal rat: a consideration of the role of desulfation of ３，５，３’-triiodothyronine sulfate as a source of T3.」Pediatr. Res. 誌1992年, 31巻, ５４１〜５４４頁Santini F., Chopra IJ., Wu SY., Solomon DH., Chua Teco GN., `` Metabolism of 3,5,3'-triiodothyronine sulfate by tissues of the fetal rat: a consideration of the role of desulfation of 3, 5, 3'-triiodothyronine sulfate as a source of T3. "Pediatr. Res., 1992, 31, 541-544 De Herder WW., Hazenberg MP., Pennock-Schroeder AM., Hennemann G., Visser TJ.著「Rapid bacteria-dependent in vitro hydrolysis of iodothyronine conjugates by intestinal contents of humans and rats.」Med. Biol. 1986年, 64巻, ３１〜３５頁De Herder WW., Hazenberg MP., Pennock-Schroeder AM., Hennemann G., Visser TJ. “Rapid bacteria-dependent in vitro hydrolysis of iodothyronine conjugates by intestinal contents of humans and rats.” Med. Biol. 1986, Volume 64, pages 31-35 Santini F., Hurd RE., Lee B., Chopra IJ.著「Thyromimetic effects of 3,5,3’-triiodothyronine sulfate in hypothyroid rats.」Endocrinology 1993年, 133巻, 1号, １０５〜１１０頁Santini F., Hurd RE., Lee B., Chopra IJ. “Thyromimetic effects of 3,5,3′-triiodothyronine sulfate in hypothyroid rats.” Endocrinology 1993, 133, 1, 105-110 Santini F., Chiovato L., Chiri P., Lapi P., Mammoli C., Montanelli L., Scartabelli G., Ceccarini G., Coccoli L., Chopra IJ., Boldrini A., Pinchera A.著「Serum iodothyronines in human fetus and the newborn: evidence for an important role of placenta in fetal thyroid hormone homeostasis.」J. Cl. Endocrinol. Metab.誌1999年, 84巻, 2号, ４９３〜４９８頁Serum by Santini F., Chiovato L., Chiri P., Lapi P., Mammoli C., Montanelli L., Scartabelli G., Ceccarini G., Coccoli L., Chopra IJ., Boldrini A., Pinchera A. iodothyronines in human fetus and the newborn: evidence for an important role of placenta in fetal thyroid hormone homeostasis. '' J. Cl. Endocrinol. Metab. 1999, 84, 2, 493-498 Santini F., Pinchera A., Ceccarini G., Castagna M., Rosellini V., Mammoli C., Montanelli L., Zucchi V., Chopra IJ., Chiovato L.著「Evidence for the role of the type III-iodothyronine deiodinase in the regulation of ３，５，３’-triiodothyronine content in the human central nervous system.」Eur. J. Endocrinol.誌2001年, 144巻, ５７７〜５８３頁Santini F., Pinchera A., Ceccarini G., Castagna M., Rosellini V., Mammoli C., Montanelli L., Zucchi V., Chopra IJ., Chiovato L., `` Evidence for the role of the type III- iodothyronine deiodinase in the regulation of 3, 5, 3'-triiodothyronine content in the human central nervous system. "Eur. J. Endocrinol. 2001, 144, 577-583 Santini F., Cortellazzi D., Baggiani AM., Marconi AM., Beck-Peccoz P., Chopra IJ.著「A study of the serum 3,5,3’-triiodothyronine sulfate concentration in normal and hypothyroid fetuses at various gestational stages.」J. Cl. Endocrinol. Metab.誌1993年, 76巻, 6号, １５８３〜１５８７頁Santini F., Cortellazzi D., Baggiani AM., Marconi AM., Beck-Peccoz P., Chopra IJ., `` A study of the serum 3,5,3'-triiodothyronine sulfate concentration in normal and hypothyroid fetuses at various gestational J. Cl. Endocrinol. Metab. 1993, 76, 6, 1583-1587 Chopra IJ., Nguyen D.著「Demonstration of thyromimetic effects of 3,5,3’-triiodothyronine sulfate (T3S) in Euthyroidrats.」Thyroid誌1996年, 6巻, 3号, ２２９〜２３２頁Chopra IJ., Nguyen D., "Demonstration of thyromimetic effects of 3,5,3'-triiodothyronine sulfate (T3S) in Euthyroidrats." Thyroid 1996, 6, 3, 229-232

結果として，今日，当業者は依然として，生成物の生物学的特性の一部だけが強調（highlits）されており，更なる研究により完全で徹底した研究が必要であるという，複雑且つ多少矛盾する状況に直面している。   As a result, today, those skilled in the art are still complex and somewhat inconsistent that only some of the biological properties of the product are highlighted, requiring further and thorough research for further research. Face the situation.

いずれにせよ，当技術分野の技術水準を形成するいずれの文献にも，Ｔ３のこの異常な代謝産物を治療に用いる可能性は，開示，教示，或いは示唆されていない。また，近似する従来技術文献のいずれにも，それが実験的性質に関する文献又は概ね理論的な文献であろうとも（それ単独でも，又は他の関連文献と組合わせても），Ｔ３Ｓ自体で，若しくは例えばＴ４等の他の甲状腺ホルモン又はプロホルモンと好適に組合わせて，薬剤として使用すること又は使用する可能性ですら，示唆する文献は存在しない。身体の一部の特定組織においてのみ，特定且つ特別の状況下で，Ｔ３ＳがＴ３に再転換されるという事実は，生成物の対外的投与を介して有機的組織体全体にこの特性を一般化することが可能であるということを意味せず，暗示せず，且つ示唆もしない。特に，生成物を経口投与することによって，その経口投与が例え周知の製薬技術による方法に従った保護的形態であったとしても，生物学的に利用可能になり得ることは，示唆されていない。なぜならば，周知のように，適切なスルファターゼが存在しない場所では，それらがすぐに代謝されて胆汁及び尿を介して***されてしまうからである。 In any case, in any of the documents forming the state of the art in the art, the possibility of use in treating the abnormal metabolites of T 3 are disclosed, taught or not suggested. Also, any approximate prior art document, whether it is an experimental property document or a generally theoretical document (either by itself or in combination with other related documents), T 3 S itself in, or for example by suitably combining with other thyroid hormones or pro-hormone of T 4, etc., even the possibility of it or used to use as a medicament, references suggesting does not exist. The fact that T 3 S is reconverted to T 3 under certain and special circumstances only in certain tissues of the body is a characteristic of this property throughout the organic tissue through the external administration of the product. Does not mean that it is possible to generalize, nor does it imply or suggest. In particular, there is no suggestion that oral administration of the product can be made bioavailable even if the oral administration is in a protective form according to well-known pharmaceutical techniques. . This is because, as is well known, where there is no appropriate sulfatase, they are quickly metabolized and excreted via bile and urine.

予想に反して，Ｔ３Ｓをそれ自体を，又は好ましくはＴ４等の他の甲状腺ホルモン又はプロホルモンと組合わせて，所望の用途に応じて適切に調合することで，特にＴ３等の活性甲状腺ホルモンの身体による生成量が必要量より不足することから生じる全ての病状に用いられる薬剤として，特に有用であることが今や判明した。また，このことは，本発明の一態様である。 Contrary to expectation, the activity of T 3 S in particular, especially by combining T 3 S itself or preferably in combination with other thyroid hormones or prohormones such as T 4 according to the desired application. It has now been found to be particularly useful as a drug for use in all medical conditions resulting from the body producing less thyroid hormone than necessary. This is also an embodiment of the present invention.

予想に反して，Ｔ３Ｓの投与が，その通常の代謝について知られていることと異なり，身体内で長時間（１２〜１８時間）の間，Ｔ３の安定した濃度の維持を可能にすること，及びその効果は，甲状腺ホルモンを最も活性な形態で補充する必要がある場合に非常に有用であることが判明した。 Contrary to expectation, administration of T 3 S, unlike what is known about its normal metabolism, allows the body to maintain a stable concentration of T 3 for an extended period of time (12-18 hours) And its effect proved to be very useful when thyroid hormone needs to be supplemented in its most active form.

特に，Ｔ３ＳのＴ４との関連に帰着する甲状腺機能低下症の治療に好適であり，これは本発明の主たる態様である。このホルモンの関係は，Ｔ４とＴ３の組合わせにより示される通常の甲状腺の分泌に，理論的に，より正確に模倣するべきである。実際，前述のヨードチロニンを両方とも含み，通常の生理学的分泌のうちの１つに類似する比率で調剤された医薬組成物が，既に試験され，且つ市販されている。残念ながら，Ｔ４及びＴ３のこの同時経口投与は，Ｔ３の薬物動態が原因で，甲状腺ホルモンの通常の血清中濃度を再現することができなかった。事実，Ｔ３は経口後，非常に素早く吸収され，同様に素早く排出される。Ｔ３の排出速度は，Ｔ４の排出速度より約２０倍，高くなっている。この理由のため，Ｔ３の経口によって，ホルモン濃度が上昇して，正常の生理学的な濃度と比較して，危険なピークを超過し，その後，非常に急速に降下して正常の生理学的な濃度以下になってしまう。この結果，今日，専門的な医師の大部分は，Ｔ４を単独で使用する方を選択する。例え，Ｔ４を単独で使用する方法によるＴ３の生成が，甲状腺による直接的なＴ３の分泌が存在しないか，又は著しく不十分であるために，末梢組織でのＴ４の脱ヨード化のみに依存するとしてもである。 It is particularly suitable for the treatment of hypothyroidism resulting in the association of T 3 S with T 4 , which is the main aspect of the present invention. The relationship between the hormone, the secretion of normal thyroid represented by a combination of T 4 and T 3, theoretically, should mimic more accurately. Indeed, pharmaceutical compositions containing both of the aforementioned iodothyronines and formulated at a ratio similar to one of normal physiological secretions have already been tested and are commercially available. Unfortunately, this simultaneous oral administration of T 4 and T 3 failed to reproduce the normal serum concentration of thyroid hormone due to T 3 pharmacokinetics. In fact, T 3 after oral, are absorbed very quickly, and is discharged similarly quickly. Discharge rate of T 3 is about 20 times higher than the discharge rate of T 4, it is higher. For this reason, by oral T 3, hormone concentration increased, as compared with physiological concentrations of normal, exceed a dangerous peak, then a very normal physiological rapidly drops It will be below the concentration. As a result, today, most of the specialized physicians, to select a person to use the T 4 alone. For example, the deiodination of T 4 in peripheral tissues because the production of T 3 by the method using T 4 alone is not or is significantly insufficient for direct T 3 secretion by the thyroid gland. Even if it depends only on.

これに反して，本発明による関連付けは，上述の問題は回避される。なぜならば，例えば経口後に，Ｔ３Ｓによって，血清中Ｔ３濃度は緩やかに増大し，長時間，安定状態が保持され，従って，非常に高いピークの形成が防止されるからである。 On the contrary, the association according to the invention avoids the above-mentioned problems. This is because, for example, after oral administration, T 3 S gradually increases the serum T 3 concentration and remains stable for a long time, thus preventing the formation of very high peaks.

Ｔ３の有機物欠乏症に起因する病状の治療にＴ３Ｓを用いることで得られる予想外の別の利点は，ＴＳＨ分泌の貧弱な抑制に関連する，最近発見された組織的な甲状腺ホルモン様活性にある。この効果は，甲状腺癌を患い甲状腺切除された患者に対して，全身シンチグラフィを行うことを考慮して，Ｔ４の投与を一時中断しなければならない場合に，特に有用である。そのような場合，Ｔ４の代わりにＴ３Ｓを投与することによって，診断検査の邪魔をすることなく，患者の必要性を解決する。 Another unexpected benefit of using T 3 S in the treatment of conditions resulting from T 3 organic deficiency is the recently discovered systematic thyroid hormone-like activity associated with poor suppression of TSH secretion It is in. This effect is particularly useful when the administration of T 4 must be suspended in consideration of whole body scintigraphy for patients with thyroid cancer who have undergone thyroidectomy. In such cases, administering T 3 S instead of T 4 solves the patient's need without disturbing the diagnostic test.

甲状腺機能低下症の治療におけるＴ３Ｓのさらに別の利点は，その自動制限能力に関するものである。実際，Ｔ３Ｓは，甲状腺ホルモンにより一部が活性化されたＩ型ＭＤによって能動的に脱ヨード化される。甲状腺機能低下症の患者では，Ｉ型ＭＤの活性が低減しており，その結果，Ｔ３Ｓの排出も遅くなっている。実際のところ，その身体上の効果が増大している。一方，過剰に投与した場合，Ｉ型ＭＤの活性が増大されて，従って，Ｔ３Ｓがより排出される。即ち，所望しない潜在的な付随的効果が制限される。 Yet another advantage of T 3 S in the treatment of hypothyroidism relates to its automatic limiting ability. In fact, T 3 S is actively deiodinated by type I MD partially activated by thyroid hormone. In patients with hypothyroidism, the activity of type I MD is reduced, resulting in slower T 3 S excretion. In fact, its physical effects are increasing. On the other hand, when administered in excess, the activity of type I MD is increased, and thus T 3 S is more excreted. That is, unwanted side effects that are undesirable are limited.

最後だが決して軽んじられない，Ｔ３Ｓのさらなる利点は，それが，身体に正常的に存在する，通常，非活性な，即ち，無毒の代謝産物であるという事実である。その結果，その投与の後に，過敏症又は不耐性の問題が存在しないことは，当然，予想できる。 A further advantage of T 3 S that is last but never disregarded is the fact that it is a normally inactive, ie non-toxic, metabolite that is normally present in the body. As a result, it can of course be expected that there will be no hypersensitivity or intolerance problems after the administration.

従って，本発明の別の主たる態様は，活性成分として，Ｔ３Ｓをそのまま，若しくは他の甲状腺ホルモンと又はプロホルモンと組合わせて含む製薬調剤に関する。特に，好適には，Ｔ４と関連付けてＴ３Ｓを含む調剤に関する。 Therefore, another main aspect of the present invention relates to a pharmaceutical preparation comprising T 3 S as an active ingredient as it is or in combination with other thyroid hormones or prohormones. In particular, it preferably relates to a formulation comprising T 3 S in association with T 4 .

前記調剤は，所望する投薬の種類に応じて，１又は２以上の活性剤の用量が異なり，或いは製薬形態の種類が異なる。さらに，それらには，製薬技術分野で従来的に用いられている賦形剤，希釈剤，非溶剤（dissolvents），溶剤，基剤(carriers)，染料，香味料，甘味料等の有用な添加物が含まれてもよい。投与の個々の必要に応じて，個別に製薬調剤の準備を行うことは，明らかに本発明の属する従来的な技術分野に含まれる。   The formulations differ in the dosage of one or more active agents or in the type of pharmaceutical form depending on the type of medication desired. In addition, useful additives such as excipients, diluents, dissolvents, solvents, carriers, dyes, flavors, sweeteners, etc., conventionally used in the pharmaceutical arts. Things may be included. It is clearly within the prior art to which the present invention pertains to the preparation of individual pharmaceutical preparations according to the individual needs of administration.

一例（当業者を全く制限しない）として，口径使用のためにＴ３Ｓは，５〜１０００μｇ，好適には１０〜５００μｇ，より好適には２５〜２５０μｇの用量範囲で投与されてよい。 As an example (without limiting the person skilled in the art at all), for caliber use, T 3 S may be administered in a dose range of 5-1000 μg, preferably 10-500 μg, more preferably 25-250 μg.

Ｔ４と関連付けて同様に用いられる場合，好適にはＴ３Ｓが１０〜５００μｇ且つＴ４が１０〜２５０μｇの範囲，より好適にはＴ３Ｓが２５〜２５０μｇ且つＴ４が２５〜２００μｇの範囲である。 When used in the same manner in association with T 4, preferably T 3 S is 10~500μg and T 4 is 10~250μg range, more preferably T 3 S is 25~250μg and T 4 is 25~200μg It is a range.

例示を目的として，複数の好適実施例のうちから，２つの代表的な経口投与の調剤を選択し，以下に記載する。当然，これらの代表的な調剤には，その他可能な変形実施例を制限する趣旨はなく，個々の病状又は特定の調剤用途に応じて，種々の投与形式，種々の用量，又は種々の成分が用いられてよい。   For illustrative purposes, two representative oral dosage formulations are selected from the preferred embodiments and described below. Of course, these representative preparations are not intended to limit other possible variations, and may vary in dosage form, dosage, or ingredients depending on the particular medical condition or specific pharmaceutical application. May be used.

例Ａ）Ｔ３Ｓを含む経口製剤 Example A) Oral formulation containing T 3 S

Figure 2011102306
Figure 2011102306

例Ｂ）Ｔ３Ｓ及びＴ４を含む経口製剤 Example B) Oral formulation containing T 3 S and T 4

Figure 2011102306
Figure 2011102306

特に，関連付けを考慮する場合，本発明の調剤には，逐次的投与が可能になるように，個々に調剤されたＴ３Ｓ及びＴ４の投与量が含まれてもよい。この場合，１の適切なキットが提供されて，それにより，必要とする治療の用法に応じて，患者によって異なり得る方法によって，前記活性成分が別個に投与されてもよい。そのような方法によって，専門医は，患者の実際のニーズに応じた処方の変更という幅の広い選択肢をとり得る。 In particular, when considering association, the formulations of the present invention may include individually dosed T 3 S and T 4 so that sequential administration is possible. In this case, one suitable kit may be provided, whereby the active ingredients may be administered separately by methods that may vary from patient to patient, depending on the treatment regimen required. Such a method allows the specialist to have a wide choice of changing the prescription according to the actual needs of the patient.

制限を意図したものでは全くなく，単に例示を目的として説明すれば，経口投与の場合には，形状及び／又は色及び／又は内容物及び／又は用量が異なる２の個別のブリスター包装を含有する１の包装が，所望の目的に適し得る。その他の可能性も存在し，同業者によって容易に利用可能である。   Not intended to be limiting in any way, but for illustrative purposes only, oral administration contains two separate blister packs of different shape and / or color and / or contents and / or dose One package may be suitable for the desired purpose. Other possibilities exist and can be readily used by peers.

本発明の医薬組成物は，例えば，自己免疫性甲状腺疾患，ホルモン生成欠陥，甲状腺切除術，先天性甲状腺機能低下症からの原発性甲状腺機能低下症（original hypothyroidism），及び，例えば甲状腺機能低下症，非甲状腺性全身疾患，絶食（fast），セレン不足等によって生じたＩ型５’−ヨードチロニンモノ脱ヨード酵素（Ｉ型ＭＤ）の活性低下等に起因する何らかの障害等の，トリヨードチロニン（Ｔ３）の有機物欠乏症に起因する病状等を治療するのに有効である。 The pharmaceutical composition of the present invention includes, for example, autoimmune thyroid disease, hormone production defect, thyroidectomy, primary hypothyroidism from congenital hypothyroidism, and, for example, hypothyroidism , Triiodothyro such as non-thyroid systemic disease, fasting, selenium deficiency, etc. caused by decreased activity of type I 5′-iodothyronine monodeiodinase (type I MD) It is effective in treating a medical condition caused by organic matter deficiency of nin (T 3 ).

本発明の医薬組成物は，例えば，自己免疫性甲状腺疾患，ホルモン生成欠陥，甲状腺切除術，先天性甲状腺機能低下症からの原甲状腺機能低下症（ｏｒｉｇｉｎａｌ ｈｙｐｏｔｈｙｒｏｉｄｉｓｍ），並びに例えば甲状腺機能低下症，非甲状腺性全身疾患，ＦＡＳＴ，セレン不足等によって生じたＩ型５’−ヨードチロニンモノ脱ヨード酵素（Ｉ型ＭＤ）の活性低下等に起因する何らかの障害等の，トリヨードチロニン（Ｔ３）の有機物欠乏症に起因する病状等を治療するのに有効である。 The pharmaceutical composition of the present invention includes, for example, autoimmune thyroid disease, hormone production deficiency, thyroidectomy, original hypothyroidism from congenital hypothyroidism, and, for example, hypothyroidism, non-hypothyroidism Triiodothyronine (T 3 ) such as any disorder caused by reduced activity of type I 5′-iodothyronine monodeiodinase (type I MD) caused by systemic thyroid disease, FAST, selenium deficiency, etc. It is effective in treating medical conditions caused by organic deficiency.

Claims (16)

薬剤として用いるトリヨードチロニン硫酸塩。   Triiodothyronine sulfate used as a drug. 甲状腺ホルモン様活性を有することを特徴とする請求項１に記載の薬剤として用いるトリヨードチロニン硫酸塩。   The triiodothyronine sulfate used as a medicine according to claim 1, which has a thyroid hormone-like activity. 有機物欠乏症に起因する病状の処置に用いることを特徴とする請求項２に記載のトリヨードチロニン硫酸塩。   The triiodothyronine sulfate according to claim 2, wherein the triiodothyronine sulfate is used for treatment of a medical condition caused by organic substance deficiency. 前記病状は，自己免疫性甲状腺疾患，ホルモン生成欠陥，甲状腺切除術，先天性甲状腺機能低下症からの原発性甲状腺機能低下症（ｏｒｉｇｉｎａｌ ｈｙｐｏｔｈｙｒｏｉｄｉｓｍ）を含むことを特徴とする請求項３に記載のトリヨードチロニン硫酸塩。   4. The avian according to claim 3, wherein the pathology includes autoimmune thyroid disease, hormone production defect, thyroidectomy, primary hypothyroidism from congenital hypothyroidism. Iodothyronine sulfate. Ｉ型５’−ヨードチロニンモノ脱ヨード酵素（type I 5’-iodothyronine monodeiodinase）の活性低下に起因する障害の治療に用いられることを特徴とする請求項２に記載のトリヨードチロニン硫酸塩。   The triiodothyronine sulfate according to claim 2, wherein the triiodothyronine sulfate is used for treatment of a disorder caused by reduced activity of type I 5'-iodothyronine monodeiodinase (type I 5'-iodothyronine monodeiodinase). . 前記Ｉ型５’−ヨードチロニンモノ脱ヨード酵素の活性低下には，多数ある原因のうち，甲状腺機能低下症，非甲状腺性全身疾患，絶食(fast)，セレン不足を含むことを特徴とする請求項５に記載のトリヨードチロニン硫酸塩。   The decrease in the activity of the type I 5′-iodothyronine monodeiodinase includes hypothyroidism, non-thyroid systemic disease, fast, and selenium deficiency among many causes. The triiodothyronine sulfate according to claim 5. トリヨードチロニン硫酸塩を活性剤として含む医薬組成物。   A pharmaceutical composition comprising triiodothyronine sulfate as an active agent. 前記トリヨードチロニンが硫酸塩は，チロキシンと関連付けて調剤されることを特徴とする請求項７に記載の医薬組成物。   The pharmaceutical composition according to claim 7, wherein the triiodothyronine is prepared by associating sulfate with thyroxine. 前記組成物は，賦形剤，希釈剤，非溶剤，溶剤，基剤，染料，香味料，甘味料等の添加物をさらに含むことを特徴とする請求項７及び８に記載の医薬組成物。   The pharmaceutical composition according to claim 7 and 8, further comprising additives such as excipients, diluents, non-solvents, solvents, bases, dyes, flavors, sweeteners, and the like. . トリヨードチロニン硫酸塩は，５〜１０００μｇの用量範囲で投与されることを特徴とする請求項７に記載の医薬組成物。   The pharmaceutical composition according to claim 7, wherein triiodothyronine sulfate is administered in a dose range of 5 to 1000 µg. トリヨードチロニン硫酸塩は，１０〜５００μｇの用量範囲で投与されることを特徴とする請求項１０に記載の医薬組成物。   The pharmaceutical composition according to claim 10, wherein triiodothyronine sulfate is administered in a dose range of 10 to 500 μg. トリヨードチロニン硫酸塩は，２５〜２５０μｇの用量範囲で投与されることを特徴とする請求項１０に記載の医薬組成物。   The pharmaceutical composition according to claim 10, wherein triiodothyronine sulfate is administered in a dose range of 25 to 250 μg. 前記関連は，トリヨードチロニン硫酸塩が１０〜５００μｇ，且つチロキシンが１０〜２５０μｇの用量範囲で投与されることであることを特徴とする請求項８に記載の医薬組成物。   9. The pharmaceutical composition according to claim 8, wherein the relation is that triiodothyronine sulfate is administered in a dose range of 10 to 500 [mu] g and thyroxine is 10 to 250 [mu] g. 前記関連は，トリヨードチロニン硫酸塩が２５〜２５０μｇ，且つチロキシンが２５〜２００μｇの用量範囲で投与されることであることを特徴とする請求項８に記載の医薬組成物。   9. The pharmaceutical composition according to claim 8, wherein the association is that triiodothyronine sulfate is administered in a dose range of 25 to 250 [mu] g and thyroxine is 25 to 200 [mu] g. 請求項８，９及び１１〜１４のいずれかに記載の医薬組成物を個々に又は逐次的に投与するためのキット。   A kit for administering the pharmaceutical composition according to any one of claims 8, 9, and 11 to 14 individually or sequentially. 請求項７〜１５のいずれかに記載の医薬組成物を調剤するためのトリヨードチロニン硫酸塩の使用方法。   Use of triiodothyronine sulfate for formulating the pharmaceutical composition according to any one of claims 7 to 15.
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